Benzopyran compounds, process for preparing the same and their use

ABSTRACT

The invention relates to the benzopyran compounds of formula (I), or the salts thereof, in which, the bond between 3 and 4 positions is a single or double bond; R 1  represents a hydrogen atom or a C 1-6  alkyl that can be substituted; R 2  represents a hydrogen atom, a C 1-6  alkyl that can be substituted or an aromatic carbocyclic or aromatic heterocyclic group that can be substituted. The invention also relates to a process for preparing such compounds or their salts as well as the use of such compounds or their salts in the preparation of the medicine against type II diabetes mellitus.

FIELDS OF INVENTION

The invention relates to the fields of pharmaceutical chemistry andendocrinotherapy, and particularly to the synthesis of benzopyrancompounds and their use in preparation of the medicine against type IIdisbetes mellitus.

BACKGROUND ART

Type II disbetes mellitus is a metabolic disturbance disease, and thepatients exhibit mainly the symptoms of increased blood sugarconcentration (the fasting blood sugar concentration is over 130 mg/dL)and glycosuria. Long-term hyperglycemia may cause the occurrence ofvarious complicating diseases, such as pathological changes in theretina, the kidney and the nervous system. Among others, thecardiovascular complicating diseases are the main cause of the diabeticpatients being dead or disabled [Shinkai, H. Exp. Opin. Ther. Patents.2000, 10: 596]. Therefore, it is very important to control the patients'blood sugar concentration for inhibiting or blocking the occurrence ofthe complicating diseases. Currently, the sulfonylurea drugs forstimulating the scretion of insulin and the biguanide drugs are usedclinically to control the patients' blood sugar concentration. Since theinsulin resistance is the main pathogenesis of the type II diabetesmellitus, the insulin-sensitizing agent is an important trend in theresearch of drugs against the type II diabetes mellitus. The firstthiozolidinedione insulin-sensitizer, troglitazone, is presented on themarket in 1997. This drug as well as other drugs of the same kindavailable on the market later, pioglitazone and rosiglitazone, cancontrol clinically the patients' blood sugar concentration well.However, the thiozolidinedione drugs exhibit the hepatotoxicity ofdifferent extents [Henry, R. R. Endocrinol. Metab. Clin. North Am. 1997,26, 553]. And the troglitazone is withdrawn from the market due to itsserious hepatotoxicity. The toxicity of this type of compounds wassuspected to be related to the thiazolidinedione group. So the study ofinsulin-sensitizers has shifted to the synthesis and development ofnon-thiazolidinedione compounds for anti-type II diabetes treatment.

One object of the present invention is to provide the novel benzopyrancompounds with the insulin-sensitizing activities and the pharmaceuticalacceptable salts thereof.

Another object of the present invention is to provide the preparativemethods for the benzyopyran compounds and their salts.

A further object of the present invention is to provide the applicationof the benzopyran compounds and their salts in the preparation of thedrugs against type II diabetes mellitus.

Methods of treating type II disbetes with the compounds of the presentinvention are also described herein.

SUMMARY OF THE INVENTION

The invention provides the benzopyran compounds represented by thefollowing formula (I) and their salts:

wherein, the bond between the 3 and 4 positions in the formula (I) is asingle bond or a double bond;

R₁ = a hydrogen atom or a linear or branched C₁—C₆ alkyl;

R₂ = a linear or branched C₁—C₆ alkyl, or an aromatic ring or aromaticheterocyclic group selected from

wherein R₃ is a linear or branched C₁—C₄ alkyl, trifluoromethyl, aminogroup, amino alkyl, nitryl, halogen or hydroxyl, n = 0-4, Y ═ N, CH.

The present invention further provides three preparative methods for thebenzopyran compounds represented by the formula (I) and their salts.

The first preparative method includes the following steps:

(1) Conducting an etherification of 7-hydroxyl-3-coumarin carboxylicacid methyl ester and halogenated benzyl, followed by hydrolyzationunder basic condition to give the compounds of formula (I), wherein R₁is CH₃ or H, and R₂ is

(2) Conducting Mitsunobu reaction of 7-hydroxyl-3-coumarin carboxylicacid methyl ester and corresponding alcohols, followed by hydrolyzationto obtain the compound of formula (I), wherein R₁ is CH₃ or H, and R₂ is

(3) Conducting catalytic hydrogenolysis of the compounds of formula (1)with the double bond between 3 and 4 positions, to obtain the compoundsof formula (1) with the single bond between 3 and 4 positions;

(4) Preparing the corresponding pharmaceutical acceptable salts in amanner known in the art.

The second preparative method includes the following steps:

(1) Mitsunobu condensing 7-hydroxyl-3-coumarin carboxylic acid methylester with t-butoxylcarbony-protected 2-methylaminoethanol, deprotectingafter hydrogenizing the resultant compounds to reduce the double bond,and condensing with 2-chlorobenzooxazole, wherein R₁ is CH₃, R₂ is

(2) Preparing the corresponding pharmaceutical acceptable salts in amanner known in the art.

The third preparative method includes the following steps:

(1) Mitsunobu condensing 7-hydroxyl-3-coumarin formic acid tert-butylester with 2-(5-methyl-2-phenyl-4-oxazole) ethanol, followed bycatalytic hydrogenation of the resultant compounds to obtain thecompounds of formula (I), wherein R₁ is tert-butyl or H, and R₂ is

(2) Preparing the corresponding pharmaceutical acceptable salts in amanner known in the art.

The present invention further provides the application of the benzopyrancompounds of formula (I) in the preparation of the drugs against type IIdiabetes mellitus.

DESCRIPTION OF THE INVENTION

Unless specified, the terms in the description have the followingdefinitions:

The phrase “C₁₋₆ alkyl” includes the saturated or unsaturated,substituted or unsubstituted linear or branched alkane-derived groupscontaining 1 to 6 carbon atoms. Specific examples include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl,isoamyl, neo-pentyl, tert-amyl, 1-methylbutyl, 2-methylpropyl, hexyl,isohexyl, 1-methylamyl, 2-methylamyl, 3-methylamyl, 2-methylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl or the like. Among these groups, the alkyls of 1to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl orthe like, are preferable. And methyl, ethyl, propyl are more preferable,methyl and ethyl are the most preferable.

The term “aryl” means an aromatic group, preferably an aryl of 6 to 14carbon atoms, and including phenyl, tolyl, xylyl, biphenyl, naphthyl,indenyl, anthryl, phenanthryl, wherein phenyl and naphthyl are morepreferable, and phenyl is the most preferable.

The term “aromatic heterocyclic group” means five- or six-memberedhetero aromatic group containing 1-4 hetero atoms selected from oxygen,nitrogen and sulfur, and including furyl, thienyl, pyrrolyl, imidazolyl,thiazolyl, pyrazolyi, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazolyl, tetrazolyl or the like. Among thesegroups, thienyl, furyl, oxazolyl, isoxazolyl and thiazolyl arepreferable, and thienyl, oxazolyl and isoxazolyl are more preferable.

The term “substituted alkyl”, “substituted aryl” and “substitutedaromatic heterocyclic group” mean that the above “alkyl”, “aryl” and“aromatic heterocyclic group” can be optionally substituted by thegroups selected from halogen atoms, alkyl, alkoxyl, acyloxy, —OH, —NH₂,—NO₂, or —NHAc.

The “pharmaceutical acceptable salts” may specifically include the saltswith inorganic acids, such as hydrochloric acid, hydrobromic acid,hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid or thelike; the acid-addtion salts with organic acids, such as formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, picric acid, methanesulfonic acid, ethylsulfonic acid orthe like, and with acidic amino acids, such as aspartic acid, glutamicacid or the like; or the salts formed with alkalis, such as the saltswith inorganic alkalis of Na, K, Ca, Al or the like, ammonium salt,methylamine salt, ethylamine salt, ethanolamine salt or the like; or thesalts formed with basic amino acids, such as lysine, arginine, ornithineor the like.

The benzopyran compounds of formula (I) and their salts in the presentinvention are prepared as follows:

In the scheme: a. halogenated benzyl, inorganic alkali; b. hydrolyzationunder the basis conditions, followed by acidification; c. R₁—OH,triphenylphosphine, diethyl azodicarboxylate; d. hydrolyzation under thebasis conditions, followed by acidification; e. catalytichydrogenolysis.

An embodiment of procedure I is as follows:

(1) Reacting 2, 4-dihydroxyl benzaldehyde with methyl malonic acid toobtain 7-hydroxyl-3-coumarin carboxylic acid methyl ester, which in turnreacts with halogenated benzyl under the basic condition to obtain thecompound 1. The suitable halogenated benzyls for the condensationreaction are chlorobenzyl, bromicbenzyl, or the like, and the suitableinorganic bases are sodium hydroxide, lithium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, lithium carbonate,etc. The condensation reaction temperature is between −10-180° C. Thesuitable solvents are the polar aprotic solvents, such asdimethylformamide, DMSO, etc. The reaction time is 0.1-72 hours. Theoptimal condensation reaction condition is to react7-hydroxyl-3-coumarin carboxylic acid methyl ester with the bromicbenzylin dimethylformamide, with the potassium carbonate as the base, at 70°C. for 0.1-12 hours.

The compound 1 is hydrolyzed under the basic condition, followed byacidification, to obtain the compound 2. The suitable inorganic basesfor the hydrolyzation are sodium hydroxide, lithium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, lithium carbonate,etc. The hydrolyzation temperature is between −10-200° C. The solventsare polar protic solvents, such as methanol, ethanol, water, etc, or themixed solvent obtained by mixing them in proportion. The reaction timeis 0.1-72 hours. The optimal hydrolyzation condition is to conduct thereaction with reflux in the 10% of sodium hydroxide aqueous solution for1 hour. The suitable acids for acidification may be the inorganic acid,such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acidor the like, or the organic acid, such as acetic acid, maleic acid,citric acid, tartaric acid, or the like.

(2) Conducting the Mitsunobu reaction of 7-hydroxyl-3-coumarincarboxylic acid methyl ester and corresponding alcohols to obtain thecompounds 3 to 6. The solvents used in the Mitsunobu reaction are theanhydrous inert solvents, such as anhydrous tetrahydrofuran, anhydrousdioxane, anhydrous benzene, anhydrous ether, chloroform, dichloromethaneor the like. The reaction temperature is between −10-100° C., thereaction time is between 0.1-72 hours. The rude product isrecrystallized with methanol, ethanol, isopropanol, ethyl acetate,chloroform and dichloromethane, or with the mixed solvent of two or moreof them in proportion. The optimal reaction condition is to conduct thereaction under room temperature for 0.1-24h with the anhydroustetrahydrofuran as solvent, and recrystallize the rude product withmethanol.

(3) Hydrolyzing the compounds 3 to 6 under the suitable condition toobtain the compounds 7 to 10 and 14. The suitable inorganic bases forthe hydrolyzation are sodium hydroxide, lithium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, lithium carbonate,etc. The hydrolyzation temperature is between 0-150° C. The solvents arethe polar protic solvents, such as methanol, ethanol, isopropanol water,or the like, the polar aprotic solvents, such as dimethylformamide anddimethylsulfoxide, or the mixed solvents of them in proportion. Thereaction time is 0.1-72 hours. The optimal hydrolyzation condition is toconduct the reaction with reflux in the 10% of sodium hydroxide aqueoussolution for 1 hour. The suitable acids for acidification are inorganicacid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoricacid or the like, or organic acid, such as acetic acid, maleic acid,citric acid, tartaric acid, or the like.

(4) Hydrogenolysing catalytically the compounds 3 to 6 to obtain thecompounds 11 to 13. The catalysts for catalytic hydrogenolysis may beselected from the 10% or 5% of palladium-carbon or Raney-Ni or othercatalysts containing palladium or nickel, and 10% of palladium-carbon ispreferable. The solvents may be selected from the lower alkyl alcohols,such as methanol, ethanol, isopropanol, etc, or other solvents, such asacetic acid, anhydrous tetrahydrofuran, anhydrous dioxane, water, or themixed solvents of two or more of them in suitable proportion. Thereaction time is from 0.1 hours until no hydrogen is absorbed. Thereaction temperature is from the room temperature to 40° C., and theroom temperature is the most preferable. The reaction pressure rangesfrom the normal pressure to scores of atmospheric pressures, and thenormal pressure is the most preferable. The solvents forrecrystallization is ethanol, methanol, isopropanol, acetone, ethylacetate, chloroform, dichloromethane, phenyl, toluene, n-hexane,n-heptane or the mixed solvents which are constituted by two or more ofthem in a suitable proportion. The preferable solvent forrecrystallization of each compound is as showed in the embodiment.

(5) Preparing the corresponding pharmaceutical acceptable saltsaccording to requirement.

In the scheme: a. triphenylphosphine, diethyl azodicarboxylate,2-(N-tert-carbobutoxy-N-methylamino)ethanol, tetrahydrofuran; b.H₂/Pd—C; c. trifluoroacetic acid, CH₂Cl₂; d. 2-chlorobenzoxazole.

An embodiment of procedure II is as follows:

(1) Conducting the Mitsunobu condensation of 7-hydroxyl-3-coumarincarboxylic acid methyl ester and t-butoxycarbonyl-protected2-methylaminoethanol to obtain the compound 15. The solvents used in theMitsunobu reaction are the anhydrous inert solvents, such as anhydroustetrahydrofuran, anhydrous dioxane, anhydrous benzene, anhydrous ether,chloroform, dichloromethane or the like, and the anhydroustetrahydrofuran is preferable. The reaction temperature is between−10-100° C., and the room temperature is preferable. The reaction timeis between 0.1-72 hours, and 24 hours is the most preferable.

(2) Deprotecting after the compound 15 is hydrogenized to reduce thedouble bond, and then condensing with 2-chlorobenzoxazole to obtain thecompound 16. The catalysts for catalytic hydrogenation may be selectedfrom the 10% or 5% of palladium-carbon or Raney-Ni or other catalystscontaining palladium or nickel, and 10% of palladium-carbon ispreferable. The solvents may be selected from the lower alkyl alcohols,such as methanol, ethanol, isopropanol, etc, or other solvents, such asacetic acid, anhydrous tetrahydrofuran, anhydrous dioxane, water, or themixed solvents constituted by two or more of them in suitableproportion. The reaction time is from 0.1 hours until no hydrogen isabsorbed. The reaction temperature is from the room temperature to 40°C., and the room temperature is the most preferable. The reactionpressure ranges from the normal pressure to scores of atmosphericpressures, the normal pressure is the most preferable.

Removal of the protective group can be conducted by stirring withtrifluoracetic acid for 48 hours at −10-80° C. The optimal reactioncondition is to stir with trifluoracetic acid for 8 hours at 0° C.

The suitable inorganic bases for condensation with 2-chlorobenzoxazoleinclude sodium hydroxide, lithium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, lithium carbonate, etc. or the organicbases include triethylamine, pyridine, diisopropylamine, etc. Thehydrolyzation temperature is −10-150° C. The solvents are the polaraprotic solvents, such as tetrahydrofuran, ether, benzene, chloroform,dichloromethane, DMF, DMSO, etc. The reaction time is 0.1-72 hours.

(3) Corresponding pharmaceutical acceptable salts are prepared accordingto requirement.

In the scheme: a. R₁—OH, triphenylphosphine, diethyl azodicarboxylate;b. i. H₂/Pd—C; ii. trifluoroacetic acid, CH₂Cl₂.

An embodiment of procedure III is as follows:

(1) 2,4-dihydroxyl benzaldehyde and tert-butyl malonic acid are reactedto obtain 7-hydroxyl-3-coumarin formic acid tert-butyl ester, which inturn is Mitsunobu condensed with 2-(5-methyl-2-phenyl-4-oxazole)ethanolto obtain the compound 17. The solvents used in Mitsunobu reaction arethe anhydrous inert solvents, such as anhydrous tetrahydrofuran,anhydrous dioxane, anhydrous benzene, anhydrous ether, chloroform,dichloromethane or the like, and the anhydrous tetrahydrofuran ispreferable. The reaction temperature is between −10-100° C., and theroom temperature is preferable. The reaction time is between 0.1-72hours, and 24 hours are preferable.

(2) The compound 17 is catalytically hydrogenized to obtain the compound18. The catalysts for catalytic hydrogenation may be selected from the10% or 5% of palladium-carbon or Raney-Ni or other catalysts containingpalladium or nickel, and 10% of palladium-carbon is preferable. Thesolvents may be selected from the lower alkyl alcohols, such asmethanol, ethanol, isopropanol, etc, or the polar aprotic solvents, suchas tetrahydrofuran, dioxane, ether, etc, or other solvents, such asacetic acid, water, etc. or the mixed solvents constituted by two ormore of the above solvents in suitable proportion, and the mixed solventof methanol/dioxane in the ratio of 1:1 is the most preferable. Thereaction time is from 0.5 hours until no hydrogen is absorbed. Thereaction temperature is from the room temperature to 40° C., and theroom temperature is the most preferable. The reaction pressure rangesfrom the normal pressure to scores of atmospheric pressures, the normalpressure is the most preferable.

Removal of the protective group can be conducted by stirring withtrifluoracetic acid for 48 hours at −10-80° C. The optimal reactioncondition is to stir with trifluoracetic acid for 8 hours at 0° C.

(3) Corresponding pharmaceutical acceptable salts are prepared accordingto requirement.

The representative benzopyran compounds of formula (I) according to thepresent invention are listed as follows:s

(1) 7-benzyloxyl-2-oxo-2H-1-benzopyran-3-carboxylic acid methyl ester;

(2) 7-benzyloxyl-2-oxo-2H-1-benzopyran-3-carboxylic acid;

(3) 7-(2-phenyl)ethoxyl-2-oxo-2H-1-benzopyran-3-carboxylic acid methylester;

(4)7-[2-(5-ethyl-2-pyridine)ethyoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid methyl ester;

(5)7-[2-(1-indole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylic acidmethyl ester;

(6)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid methyl ester;

(7) 7-(2-phenyl)ethoxyl-2-oxo-2H-1-benzopyran-3-carboxylic acid;

(8)7-[2-(5-ethyl-2-pyridine)ethyoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid;

(9) 7-[2-(1-indole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylic acid;

(10)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid;

(11) 7-(2-phenyl)ethoxyl-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid methyl ester;

(12)7-[2-(5-ethyl-2-pyridine)ethyoxyl]-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid methyl ester;

(13)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-3,4-dihydro-2-oxo-4H-1-benzopran-3-carboxylicacid methyl ester;

(14)7-(4-trifluoromethylbenzyloxyl)-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid methyl ester;

(15)7-[2-(N-tert-butoxycarbonyl-N-methylamino)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid methyl ester;

(16)7-[2-[N-methyl-N-(2-benzoxazole)amino]ethoxyl]-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid methyl ester;

(17)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid tert-butyl ester;

(18)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid.

The structure formulas of the above-mentioned compounds 1-18 see table1.

TABLE 1

Double bond Com- between pound positions No. R2 R1 3 and 4^(a) 1

CH₃ Yes 2

H Yes 3

CH₃ Yes 4

CH₃ Yes 5

CH₃ Yes 6

CH₃ Yes 7

H Yes 8

H Yes 9

H Yes 10

H Yes 11

CH₃ No 12

CH₃ No 13

CH₃ No 14

CH₃ No 15

CH₃ Yes 16

CH₃ No 17

t-Bu Yes 18

H No ^(a)Yes: double bond between positions 3 and 4; No: single bondbetween positions 3 and 4

Evaluation of biological activities:

The insulin-sensitizing agents can promote the differentiation ofpre-adipocytes toward adipocyte. Thus insulin-sensitizing agents couldbe identified with the insex of the differentiation of pre-adipocytes.Following the methods reported in the literature [Kletzein B F. Mol.Pharm. 1991, 41, 393], the insulin-sensitizing activities of thecompounds of formula (I) of the present invention were evaluated in3T3-L1 preadipocyte model with triglyceride accumulation in cells as theindication of cell differentiation.

The 3T3-L1 cells were incubated in DMEM (Dulbecco's Modified Eagle'sMedium) containing 10% NBS (newborn calf serum) and subcultured every 3days. The cells were transferred to 24-pore plates, and after the poreswere filled completely, the cells were treated with IBMX(isobutylmethylxanthine) (0.5 mmol/L), DEX (dexamethasone) (1 μmol/L)and insulin (1.0 μmol/L) for 48 h, meanwhile different amounts of testcompounds were added into. The cells were incubated continuously untilthe end of the experiment. Cells were collected and the contents oftriglyceride and protein therein were determined by colorimetry.Enhancements of triglyceride in cells after drug-administrating werecalculated.

The positive control group was rosiglitazone, and the solvent controlgroup was a culturing medium containing 0.1% of DMSO. The enhancement oftriglyceride in cells of three different concentrations (0.01, 0.1, 1μmol/L) of each tested compounds is presented in Table 2, from which itcan be see that the compounds 6, 13, 17, 18, etc have strongerinsulin-sensitizing activity. Thus, the derivatives of the benzopyrancompounds of the present invention can be used to control the bloodglucose level in type II diabetes patients and inhibit the occurrence ofcomplications caused by the type II diabetes.

The benzopyran compounds of the present invention do not contain athiazolidinedione group, but possess the similar insulin-sensitizingactivity as that of the thiazolicinedione compounds. Therefore, it ispossible that the compounds disclosed herein will be developed as thenovel medicaments for treatment of type II diabetes.

TABLE 2 The Percentage of Triglyceride Increased in 3T3-L1 CellsConcentration of the test compounds (μmol/L) Compound No. 0.01 0.1 1 1−5.73 −0.43 7.93 2 20.86 18.31 14.63 3 4.57 −2.61 −5.50 4 7.26 11.5517.71 5 7.88 27.58 34.74 6 27.04 67.24 52.45 7 7.97 −1.10 −6.29 8 12.253.67 5.66 9 −5.25 −8.42 −12.95 10 −3.28 26.68 32.30 11 −9.13 12.90 14.1012 4.13 −2.40 2.53 13 28.33 52.92 64.69 14 19.33 −16.81 −2.69 15 26.3826.73 44.70 16 11.01 29.32 25.09 17 18.33 28.20 33.01 18 18.65 29.2830.24 Rosiglitazone^(b) 27.20 ± 2.35 34.93 ± 2.14 39.21 ± 2.27^(a)Average data in 3 pores. ^(b)Sample number n = 22; The value in thetable is the mean value of enhancement of triglyceride ± SD. ND: NotDone.

The compounds of the present invention and their pharmaceuticalacceptable salts may be prepared into many forms of preparations, whichcontain a safe and effective dosage of the compounds or theirpharmaceutical acceptable salts in the present invention, and thepharmaceutical acceptable carrier.

“Safe and effective dosage” means the amount of the compounds that aresufficient to improve significantly the condition of patients, but donot lead to serious side effects. The safe and effective dosage ofcompounds is determined according to the age, condition, and course oftreatment of the subjects accepting the therapy and will usually bedeterminable by one of ordinary skill by routine experimentation.

“Pharmaceutical acceptable carrier” refers to one or many kinds ofcompatible solid or liquid packing materials or gelling substances,which are suitable for human use and have enough purity and lowtoxicity. “compatible” is used to indicate that each component in thecompositions can mixed with the compounds of the present invention andwith each other without significantly impairing the drug action of thecompounds. Some examples of the pharmaceutical acceptable carrierinclude cellulose and its derivatives (CMC—Na, EC—Na, cellulose aceticacid ester etc.), gelatin, steatite, solid lubricants (such as stearicacid, magnesium stearate), CaSO₄, vegetable oils (such as soya oil,sesame oil, peanut oil, olive oil etc.), polybasic alcohol (such aspropylene glycol, glycerin, mannitol, sorbierite etc.), emulsifyingagent (such as tweens®), moistening agent (such as sodiumdodecylsulfate), coloring agent, flavoring agent, stabilizer,antioxidant, antiseptic, pyrogen-free water, etc.

THE PREFERABLE EMBODIMENTS OF THE INVENTION

The present invention will be further explained with reference to thefollowing examples, but they don't limit the present invention in anyway. In all examples, the melting points were measured with MEL-TEMPmelting point apparatus and the thermometer was not calibrated; ¹H NMRspectra were recorded on a Varian Mercury 400 NMR spectrometer, thechemical shifts are expressed as δ (ppm); silica gel for separation is200-300 mesh unless otherwise specified.

EXAMPLE 1 7-benzyloxyl-2-oxo-2H-1-benzopyran-3-carboxylic acid methylester (compound 1)

7-hydroxyl-3-coumarin carboxylic acid methyl ester (0.2g, 1 mmol) isdissolved in N,N′-dimethyl formamide (2 mL), and bromobenzyl (0.36 ml, 3mmol) and levigated potassium carbonate (0.5 g) are added into. Theresulting mixture is stirred for 12 hours at 70° C. After adding 10 mLof water, extraction is conducted with ethyl acetate, and all of ethylacetate are combined, followed by washing with water, drying onanhydrous sodium sulfate. Then the solution is concentrated underreduced pressure to approximately 5 mL and is placed to separate out asolid, followed by filtering under reduced pressure to obtain 0.21 g ofthe captioned compound, yield: 67.7%. m.p.129-130° C. ¹H NMR(CDCl₃):δ=3.92(s, 3H), 5.19(s, 2H), 6.85(d, J=2.4 Hz, 1H), 6.95(dd, J=8.8 Hz,2.4 Hz, 1H), 7.40(m, 5H), 7.52(d, J=8.8 Hz, 1H), 8.55(s, 1H); ElementsAnalysis, C₁₈H₁₄O₅ (310): Calculated C, 69.68; H, 4.52. Found C, 69.63;H, 4.51; IR(KBr) : 3054.7, 2948.7, 1749.1, 1697.1, 1610.3, 1558.2,1500.4, 1438.7, 1378.9, 1226.5, 1116.6, 1026, 794.5, 725.1, 692.3, 636.4cm⁻¹; EI-MS(m/z): 310(12, M⁺), 91(100).

EXAMPLE 2 7-benzyloxyl-2-oxo-2 H-1-benzopyran-3-carboxylic acid(compound 2)

The compound 1 (0.1 g, 0.32 mmol) is dissolved in ethanol (0.5 mL), and10% of sodium hydroxide aqueous solution (0.5 mL) is added into. Theresulting mixture is reacted for 1 hour with reflux. After cooling, thestrong hydrochloric acid (0.3 mL) is added and followed by stirring for10 minutes. 5 mL of water is added, and produced solid is obtained byfiltration. The filter cake is washed with water, followed by drying toobtain 0.09 g of the captioned compound, yield: 90%. m.p. 196-197° C. ¹HNMR (DMSO-d6): δ=5.25(s, 2 H), 7.08(dd, J=2.2 Hz, 8.8 Hz, 1H), 7.12(d,J=2.2 Hz, 1H), 7.30-7.50(m, 5H), 7.83(d, J=8.8 Hz, 1H), 8.73(s, 1H);Elements Analysis, C₁₇H₁₂O₅ (296): Calculated C, 68.92; H, 4.05; FoundC, 68.50; H, 4.12; IR(KBr) : 3054.7, 1747.2, 1677.8, 1600.7, 1556.3,1421.3, 1378.9, 1257.4, 1209.2, 1120.2, 732.8 cm⁻¹; EI-MS(m/z): 296(4,M⁺), 91(100).

EXAMPLE 3 7-(2-phenyl)ethoxyl-2-oxo-2H-1-benzopyran-3-carboxylic acidmethyl ester (compound 3)

7-hydroxyl-3-coumarin carboxylic acid methyl ester (0.6g, 3 mmol) and2-phenyl ethanol (0.36 mL, 3 mmol) are dissolved in anhydroustetrahydrofuran (60 mL). Triphenylphosphine (1.2 g, 4.5 mmol) is added,and diethyl azodicarboxylate (0.72 mL, 4.5 mmol) is added dropwise andslowly at 0° C. The resulting solution is stirred for 24 hours at roomtemperature. After the solvent was removed under reduced pressure, theresidue is diluted with methanol and a white solid is separated out. Thesolid is recrystallized with methanol to give 0.45 g of the captionedcompound, yield: 46.3%. m.p. 100-101° C. ¹H NMR(CDCl₃): δ=3.12(t, J=6.8Hz, 2H), 3.92(s, 3H), 4.14(t, J=7.1 Hz, 2H), 6.79(d, J=2.4 Hz, 1H),6.88(dd, J=2.4 Hz, 8.8 Hz, 1H), 7.21-7.35(m, 5H), 7.47(d, J=8.7 Hz, 1H),8.50(s, 1H); Element Anyalysis, C₁₉H₁₆O₅ (324): Calculated C, 70.37; H,4.94. Found C, 70.25; H, 4.93; IR(KBr) :3045.1, 2952.5, 1751.1, 1693.2,1610.3, 1554.4, 1506.2, 1436.7, 1375, 1307.5, 1222.7, 1114.7, 1018.2,835, 749.5, 738.6, 700, 594 cm⁻¹; EI-MS(m/z): 324(24, M⁺), 105(100).

EXAMPLE 47-[2-(5-ethyl-2-pyridine)ethyoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid methyl ester (compound 4)

With 2-(5-ethyl-2-pyridine)ethanol and 7-hydroxyl-3-coumarin carboxylicacid methyl ester as starting material, the captioned compound wasprepared by the same method as in example 3, yield: 50.5%. m.p. 99-100°C. ¹H NMR(CDCl₃): δ=1.24(t, J=7.7 Hz, 3H), 2.65(m, J=7.7 Hz, 2H),3.28(t, J=6.6 Hz, 2H), 3.92(s, 3H), 4.45(t, J=6.6 Hz, 2H), 6.80(d, J=2.2Hz, 1H), 6.90(dd, J=8.5 Hz, 2.2 Hz, 1H), 7.20(d, J=8.0 Hz, 1H), 7.45(d,J=8.5 Hz, 1H), 7.55(dd, J=7.9 Hz, 2.2 Hz, 1H), 8.40(d, J=2.2 Hz, 1H),8.55(s, 1H); Element Analysis, C₂₀H₁₉NO₅ (353): Calculated C, 67.99; H,5.38; N, 3.97. Found C, 67.96; H, 5.43; N, 3.87; IR(KBr) : 2696.9,1758.8, 1693.2, 1616.1, 1560.2, 1442.5, 1376.9, 1309.4, 1226.5, 1114.7,1022.1, 792.6, 590.1 cm⁻¹; EI-MS(m/z): 277(100), 353(8, M⁺).

EXAMPLE 5 7-[2-(1-indole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid methyl ester (compound 5)

With 2-(1-indole)ethanol and 7-hydroxyl-3-coumarin carboxylic acidmethyl ester as staring material, the rude product of the captionedcompound was prepared by the same method as in example 3, and the rudeproduct is insoluble in the methanol. The rude product is refluxed withmenthol for 10 minutes, and then cooled down, followed by filtratingunder reduced pressure to give the captioned compound, yield: 72.1%.m.p. 136-137° C. ¹H NMR(CDCl₃): δ=3.90(s, 3H), 4.35(t, J=5.3 Hz, 2H),4.58(t, J=5.3 Hz, 2H), 6.50(d, J=3.4 Hz, 1H), 6.71(d, J=2.4 Hz, 1H),6.80(dd, J=2.0 Hz, 8.3 Hz, 1H), 7.10(t, J=7.3 Hz, 1H), 7.18(d, J=2.9 Hz,1H), 7.21(m, 1H), 7.40(d, J=8.3 Hz ,1H), 7.43(d, J=8.8 Hz, 1H), 7.62(d,J=7.8 Hz, 1H), 8.48(s,1H); Element Analysis, C₂₁H₁₆NO₅ (362): CalculatedC, 69.61; H, 4.42; N,3.34. Found C, 69.44; H, 4.69; N, 3.85; EI-MS(m/z):363 (40, M⁺+1), 130 (100).

EXAMPLE 67-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid methyl ester (compound 6)

2-(5-methyl-2-phenyl-4-oxazole)ethanol (0.38 g, 1.85 mmol) and7-hydroxyl-3-coumarin carboxylic acid methyl ester (0.37 g, 1.85 mmol)are dissolved in anhydrous tetrahydrofuran (40 mL). Triphenylphosphine(0.726 g, 2.78 mmol) is added, and diethyl azodicarboxylate (438 μL,2.78 mmol) is added dropwise and slowly at 0° C. The resulting solutionis stirred for 24 hours at room temperature. After the solvent wasremoved under reduced pressure, the residue is diluted with methanol anda solid is separated out, followed by filtrating under reduced pressureto give 0.38 g of the captioned compound, yield: 51.3%. m.p. 139-140° C.(Decomposed). ¹H NMR(CDCl₃): δ=2.36(s, 3H, oxazole-CH₃), 3.02(t, J=6.6Hz, 2H, oxazole-CH₂—), 3.91(s, 3H, OCH₃), 4.34(t, J=6.5 Hz, 2H, H₂C—O),6.80(d, J=2.2 Hz, 1H, 8-H), 6.85(dd, J=8.7 Hz, 2.3 Hz, 1H, 6-H), 7.40(m,3H, Ph—H), 7.46(d, J=8.8Hz, 1H, 5-H), 7.96(m, 2H), 8.50(s, 1H, 4-H);Element Analysis, C₂₃H₁₉NO₆ (405): Calculated C, 68.15; H, 4.69; N,3.46. Found C, 68.22; H, 4.98; N, 3.50; IR(KBr) : 3072.1, 1762.6,1697.1, 1612.2, 1558.2, 1376.9, 1313.3, 1222.7, 1139.7, 1016.3, 709.7cm⁻¹; EI-MS(m/z): 405(16, M⁺), 186(100).

EXAMPLE 7 7-(2-phenyl)ethoxyl-2-oxo-2H-1-benzopyran-3-carboxylic acid(compound 7)

With the compound 3 as starting material, the captioned compound wasprepared by the same method as in example 2, yield: 92%. m.p. 150-151°C. ¹H NMR(DMSO-d6): δ=3.08(t, J=6.8 Hz, 2H), 4.35(t, J=6.8 Hz, 2H),6.98(dd, J=2.5 Hz, 8.5 Hz, 1H), 7.04(d, J=2.5 Hz, 1H), 7.18-7.34(m, 5H),7.80(d, J=8.8 Hz, 1H), 8.70(s, 1H), 12.95(s, 1H, COOH); ElementAnalysis, C₁₈H₁₄O₅ (310): Calculated C, 69.68; H, 4.52. Found C, 69.55;H, 4.34; IR(KBr) :2952.5, 1741.4, 1679.7, 1618, 1556.3, 1425.2, 1382.7,1257.4, 1213, 1122.4, 808, 698.1 cm⁻¹; EI-MS(m/z): 310(3, M⁺), 105(100).

EXAMPLE 87-[2-(5-ethyl-2-pyridine)ethyoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid (compound 8)

With the compound 4 as starting material, the captioned compound wasprepared by the same method as in example 2, yield: 91%. m.p.130-131° C.¹H NMR(DMSO-d6): δ=1.28(t, J=7.5 Hz, 3H), 2.81(m, J=7.5 Hz, 2H), 3.53(m,2H), 4.58(t, J=6.4 Hz, 2H), 6.95(dd, J=8.7 Hz, 2.0 Hz, 1H), 7.15(d,J=2.0 Hz, 1H), 7.80(d, J=8.7 Hz, 1H), 7.98(d, J=7.9 Hz, 1H), 8.40(d,J=8.3 Hz, 1H), 8.70(s, 1H), 8.75(s, 1H); Element Analysis,C₁₉H₁₇NO₅.2H₂O(375): Calculated C, 60.80; H, 5.60; N, 3.73. Found C,60.34; H, 5.27; N, 3.70; IR(KBr) : 3548.4, 3477.1, 3369.1, 3045.1,2969.9, 2630.5, 1741.4, 1689.4, 1612.2, 1556.3, 1540.2, 1382.7, 1226.5,1180.2, 1016.3, 798.4 cm⁻¹; EI-MS(m/z): 339(8, M⁺), 134(100).

EXAMPLE 9 7-[2-(1-indole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid (compound 9)

With the compound 5 as starting material, the captioned compound wasprepared by the same method as in example 2, yield: 91%. m.p. 166-168°C. ¹H NMR(DMSO-d6): δ=4.42(t, J=5.0 Hz, 2H), 4.60(t, J=5.3 Hz, 2H),6.43(m, 1H), 6.90(dd, J=2.4 Hz, 8.8 Hz, 1H), 7.00(m, 2H), 7.12(m, 1H),7.41(d, J=3.3 Hz, 1H), 7.52(m, 2H), 7.78(d, J=8.8 Hz, 1H), 8.68(s, 1H),12.98(s, 1H); Element Analysis, C₂₀H₁₄NO₅ (348): Calculated C, 68.97; H,4.02; N, 4.02. Found C, 68.38; H, 4.36; N, 3.93; IR(KBr) : 3058.6,2971.8, 1764.6, 1637.9, 1602.6, 1554.4, 1508.1, 1380.8, 1276.7, 1226.5,1139.7, 800.3, 732.8 cm⁻¹; EI-MS(m/z): 349(9, M⁺+1), 105(100).

EXAMPLE 107-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid (compound 10)

With the compound 6 as starting material, the captioned compound wasprepared by the same method as in example 2, yield: 91%. m.p.142-143° C.¹H NMR(DMSO-d6): δ=2.38(s, 3H, oxazole-CH₃), 2.78(t, J=6.8 Hz, 2H,—CH₂—C), 4.37(t, J=6.9 Hz, 2H, CH₂—O), 7.01(dd, J=2.5 Hz, 8.3 Hz, 1H,6-H), 7.06(d, J=2.4 Hz, 1H, 8-H), 7.48(m, 3H, Ph—H),7.81(d, J=8.8 Hz,1H, 5-H), 7.90(m, 2H, Ph—H), 8.71(s ,1H, 4-H), 13.0(s, 1H, COOH);Element Analysis, C₂₂ H₁₇NO₆.⅔H₂O(403): Calculated C, 65.51; H, 4.55; N,3.47. Found C, 65.23; H, 4.41; N, 3.32; IR(KBr): 3054.7, 1749.1, 1679.7,1554.4, 1508.1, 1378.9, 1257.4, 1211.1, 1141.7, 800.3, 690.4 cm⁻¹;EI-MS(m/z): 391(28, M⁺), 91(100); HRMS: 391.1047 (C₂₂ H₁₇NO₆).

EXAMPLE 117-(2-phenyl)ethoxyl-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylic acidmethyl ester (compound 11)

The compound 3 (0.62 g, 1.58 mmol) is dissolved in the mixed solvent ofmethanol (3 mL) and dioxane (1 mL), and 10% of Pd—C (0.2 g) is addedinto the solution. The resulting solution is hydrogenized under thenormal pressure until no further hydrogen is absorbed. The mixture isfiltrated to remove Pd—C, and the solvent is removed under reducedpressure to give 0.6 g of the captioned compound, yield: 95%. ¹HNMR(CDCl₃): δ=2.97(t, J=6.7 Hz, 2H), 3.10(dd, J=5.9 Hz, 15.8 Hz, 1H),3.35(dd, J=8.8 Hz, 16.1 Hz, 1H), 3.75(m, 4H), 4.22(t, J=6.6 Hz, 2H),6.70(d, J=2.3 Hz, 1H), 6.79(dd, J=8.8 Hz, 2.3 Hz, 1H), 6.98(d, J=8.8 Hz,1H), 7.43(m, 3H), 7.99(m, 2H); Element Analysis, C₁₉H₁₈O₅.⅓H₂O(332):Calculated C, 68.67; H, 5.62. Found C, 68.87; H, 5.71 ;IR(KBr) :3479,2933.2, 1758.8, 1735.6, 1631.5, 1511.9, 1434.8, 1357.7, 1286.3, 1213,1164.8, 1118.5, 1022.1, 759.8, 705.8, 609.4 cm⁻¹; EI-MS(m/z): 326(12,M⁺), 105(100).

EXAMPLE 127-[2-(5-ethyl-2-pyridine)ethyoxyl]-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid methyl ester (compound 12)

With the compound 4 as starting material, the captioned compound wasprepared by the same method as in example 11, yield: 96%. m.p. 85-86° C.(decomposed). ¹H NMR(CDCl₃): δ=1.24(t, J=7.7 Hz, 3H), 2.62(m, J=7.7 Hz,2H),3.15(dd, J=6.2 Hz, 15.9 Hz, 1H), 3.21(t, J=6.8 Hz, 2H), 3.35(dd,J=8.4 Hz, 15.9 Hz, 1H), 3.65(m, 4H), 4.30(t, J=6.8 Hz, 2H), 6.80(d,J=2.6 Hz, 1H), 6.88(dd, J=8.5 Hz, 2.6 Hz, 1H), 7.15(d, J=8.2 Hz, 1H),7.20(d, J=8.1 Hz, 1H), 7.48(dd, J=7.9 Hz, 2.2 Hz, 1H), 8.40(d, J=2.0 Hz,1H); Element Analysis, C₂₀H₂₁NO₅ (355): Calculated C, 67.61; H, 5.92; N,3.94. Found C, 67.52; H, 5.84; N, 3.78; IR (KBr): 2960.2, 1700.4,1737.6, 1629.6, 1510, 1434.8, 1371.2, 1292.1, 1203.4, 1161, 1124.3,1031.7, 848.5, 800.3, 607.5 cm⁻¹; El-MS (m/z): 355(4, M⁺), 121(59),134(100).

EXAMPLE 137-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid methyl ester (compound 13)

The compound 6 (0.05 g, 0.14 mmol) is dissolved in the mixed solvent ofmethanol (1.5 mL) and dioxane (3 mL), and 10% of Pd—C (0.05 g) is addedinto the solution. The resulting solution is hydrogenized under thenormal pressure until no further hydrogen is absorbed. The mixture isfiltrated to remove Pd—C. After the solvent was removed under reducedpressure, the residue is diluted with methanol and a solid is separatedout, followed by filtrating under reduced pressure to give 0.4 g of thecaptioned compound, yield: 80.0%. ¹H NMR(CDCl₃): δ=2.37(s, 3H), 2.97(t,J=6.5 Hz, 2H), 3.08(dd, J=15.9 Hz, 6.1 Hz, 1H), 3.34(dd, J=15.7 Hz, 8.6Hz, 1H), 3.73(m, 4H), 4.22(t, J=6.4 Hz, 2H), 6.60(d, J=2.2 Hz, 1H),6.64(dd, J=8.5 Hz, 2.3 Hz, 1H), 7.06(d, J=8.4 Hz, 1H), 7.41(m, 3H),7.99(m, 2H); Element Analysis, C₂₃H₂₁NO₆ (407): Calculated C, 67.81; H,5.16; N, 3.44. Found C, 67.81; H, 5.16; N, 3.43; IR(KBr) : 2919.7,1754.9, 1731.8, 1629.6, 1510, 1444.4, 1365.4, 1292.1, 1161, 1147.5,1120.5, 800.3, 713.5, 686.5 cm⁻¹; EI-MS(m/z): 407(20, M⁺), 186(100).

EXAMPLE 147-(4-trifluoromethylbenzyloxyl)-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid methyl ester (compound 14)

4-trifluoromethylbenzalcohol (70 μL, 0.5 mmol) and7-hydroxyl-3,4-dihydro-3-coumarin carboxylic acid methyl ester (0.1 g,0.5 mmol) are dissolved in anhydrous ether (8 mL). Triphenylphosphine(0.19 g, 0.75 mmol) is added, and diethyl azodicarboxylate (120 μL, 0.75mmol) is added dropwise and slowly at 0° C. The resulting solution isstirred for 24 hours at room temperature. After the solvent was removedunder reduced pressure at 30° C., the residue is mixed with methanol atroom temperature. A solid is produced by filtrating under reducedpressure and 0.12 g of the captioned compound is obtained, yield: 61%.m.p. 138-139° C. ¹H NMR(CDCl₃): δ=3.35(d, 13.6 Hz, 1H), 3.50(d, 13.8 Hz,1H), 3.60(m, 4H), 5.09(s, 2H), 6.62(d, J=2.5 Hz, 1H), 6.70(dd, J=8.4 Hz,2.3 Hz, 1H), 7.05(d, J=8.4 Hz, 1H), 7.40(d, J=8.3 Hz, 2H), 7.65(d, J=8.3Hz, 2H); Element Analysis, C₁₉H₂₅F₃O₅(380): Calculated C, 60.00; H,3.95. Found C, 60.43; H, 3.77; IR(KBr): 3068.2, 1768.4, 1724.1, 1625.7,1510.0, 1332.6, 1243.9, 1162.9, 1068.4, 829.3 cm⁻¹; EI-MS(m/z): 380(4,M⁺), 159(100); HRMS: 380.0846(C₁₉H₁₅F₃O₅).

EXAMPLE 157-[2-(N-tert-butoxycarbonyl-N-methylamino)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid methyl ester (compound 15)

2-(N-tert-butoxycarbonyl-N-methylamino)ethanol (0.5 g, 3 mmol) and7-hydroxyl-3-coumarin carboxylic acid methyl ester (0.6 g, 3 mmol) aredissolved in 60 mL of anhydrous tetrahydrofuran. Triphenylphosphine (1.2g, 4.5 mmol) is added, and diethyl azodicarboxylate (720 μL, 0.45 mmol)is added dropwise and slowly at 0° C. The resulting solution is stirredat room temperature for 24 hours. After the solvent was removed underreduced pressure at 30° C., the residue is mixed with methanol at roomtemperature. A solid is produced by filtrating under reduced pressureand 0.83 g of the captioned compound is obtained, yield: 72.6%. m.p.128-129° C. ¹H NMR(DMCO-d6): δ=1.40(s, 9H), 2.96(s, 3H), 3.65(s, 2H),3.81(s, 3H), 4.32(s, 2H), 6.94(d, J=2.2 Hz, 1H), 7.00(dd, J=2.2 Hz, 8.4Hz, 1H), 7.80(d, J=8.8 Hz, 1H), 8.60 (s,1H); EI-MS(m/z): 377(1, M⁺),102(100).

EXAMPLE 167-[2-[N-methyl-N-(2-benzoxazole)amino]ethoxyl]-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid methyl ester (compound 16)

The compound 15 (0.55 g, 1.46 mmol) is dissolved in the mixed solvent ofmethanol (5 mL) and dioxane (15 mL), and 10% of Pd—C (0.1 g) is addedinto the solution. The resulting solution is hydrogenized under thenormal pressure until no further hydrogen is absorbed. The mixture isfiltrated to remove Pd—C, followed by removing the solvent under reducedpressure to give 0.54 g of the white-like solid. The solid is dissolvedinto the dichloromethane (1.7mL), followed by adding 1.7 mL of thetrifluoracetic acid. The resulting mixture is stirred for 8 hours at 0°C. After removing a part of solvent under the reduced pressure at roomtemperature, the residue solution is adjusted to weak alkalescence withsaturated NaHCO₃ aqueous solution and extracted withdichloromethane(2×10 mL). The combined dichloromethane were washed withH₂O, dried on anhydrous MgSO₄, and filtered under reduced pressure. Thesolvent is evaporated off from the filtrate to give 0.35 g of whitesolid. The solid is dissolved into tetrahydrofuran (5 mL),2-chlorobenzoxazole (0.4 g, 2.6 mmol) and triethylamine (0.72 mL, 5.2mmol) are added at 0° C. The mixture is stirred for 12 hours at roomtemperature. After the tetrahydrofuran is removed under the reducedpressure, the residue is dissolved in the ethyl acetate (10 mL), andwashed with water (10 mL). The phase of ethyl acetate is separated, anddried on anhydrous sodium sulphate. After the ethyl acetate is removedunder the reduced pressure, the residue is chromatographed over silicagel column with petroleum/ethyl acetate (3:4) as eluent to obtain 0.28 gof the captioned compound, yield: 50.1%. m.p. 88-90° C. ¹ H NMR(CDCl₃):δ=3.10(dd, J=6.1 Hz, 16.0 Hz, 1H), 3.33(m, 4H), 3.72(m, 4H), 3.92(t,J=5.2 Hz, 2H), 4.23(t, J=5.1 Hz, 2H), 6.61(d, J=2.6 Hz, 1H), 6.65(dd,J=2.4 Hz, 8.3 Hz, 1H), 7.00(m, 1H), 7.08(d J=8.4 Hz, 1H), 7.16(m, 1H),7.26(d, J=7.9 Hz, 1H), 7.36(d, J=7.8 Hz, 1H); Element Analysis,C₂₁H₂₀N₂O₆ (396): Calculated C, 63.60; H, 5.05; N, 7.07. Found C, 63.76;H, 5.00; N, 6.80; IR (KBr): 2935.2, 1768.4, 1735.6, 1648.9, 158.2, 1510,1459.9, 1434.8, 1292.1, 1240, 1161, 1145.5, 1002.8, 800.3, 734.8 cm⁻¹;EI-MS(m/z): 396(12, M⁺), 148(100).

EXAMPLE 177-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid tert-butyl ester (compound 17)

2,4-dihydroxylbenzaldehyde (0.27 g, 2 mmol) and di-tert-buty malonicacid (0.43 g, 2 mmol) are dissolved in tert-butanol (5 mL), and threedrops of piperidine are added. The mixture is refluxed for 16 hours toobtain a suspension. After being placed for cooling, insoluble materialis removed by filtrating. The mother liquor is concentrated, and theethyl acetate is added with stirring. The supernatant is separated,concentrated, and chromatographed over silica gel column withpetroleum/ethyl acetate (3:4) as eluent to obtain 0.14 g of7-hydroxyl-3-coumarin carboxylic acid tert-butyl ester, yield: 22.5%.

The captioned compound is produced by the same method as in example 6with 2-(5-methyl-2-phenyl-4-oxazole) and 7-hydroxyl-3-coumarincarboxylic acid tert-butyl ester as the starting material yield: 36%.m.p.140-142° C. ¹H NMR(DMCO-d6): δ=1.58(s, 9H), 2.42(s, 3H), 3.04(t,J=6.6 Hz, 2H), 4.46(t, J=6.6 Hz, 2H), 6.95(d, J=2.2 Hz, 1H), 6.99(dd,J=8.8 Hz, 2.2 Hz, 1H), 7.50(m, 3H), 7.73(d, J=8.4 Hz, 1H), 7.99(m, 2H),8.53(s, 1H); Element Analysis, C₂₆H₂₅NO₆ (447): Calculated C, 69.80; H,5.59; N, 3.13. Found C, 69.79; H, 5.57; N, 3.16; IR(KBr): 2979.5,1747.2, 1708.6, 1612.2, 1508.1, 1371.2, 1226.5, 1164.8, 1014.4, 833.1,690.4 cm⁻¹.

EXAMPLE 187-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid (compound 18)

The compound 17 (70 mg, 1.56 mmol) is dissolved in the mixed solvent ofmethanol/dioxane (1:1) (8 mL), and 10% of Pd—C (0.05 g) is added intothe solution. The resulting solution is hydrogenized under the normalpressure until no further hydrogen is absorbed. The mixture is filtratedto remove Pd—C, followed by removing the solvent under reduced pressureto obtain a oily substance (0.05 g). 0.01 g of the oily substance isdissolved into the dichloromethane (0.5 mL), followed by adding 0.5 mLof the trifluoracetic acid. The resulting mixture is stirred for 1 hourat room temperature. After removing a part of solvent under the reducedpressure, 5 mL of water is added into the residue solution, followed byextracting with ethyl acetate (2×5 mL). The combined ethyl acetate werewashed with H₂O, dried on anhydrous MgSO₄, and filtered. The filtrate isconcentrated into approximately 3 mL, and is placed at −20° C. to givewhite precipitate. The precipitate is filtered under reduced pressureand dried to give 7 mg of the captioned compound, yield: 13%. m.p.124-125° C. ¹H NMR(DMSO-d6): δ=2.37(s, 3H), 2.91(t, J=6.6 Hz, 2H),3.18(m, 2H), 3.92(t, J=6.2 Hz, 1H), 4.22(t, J=6.6 Hz, 2H), 6.72(m, 2H),7.20(d, J=8.1 Hz, 1H), 7.50(m, 3H), 7.90(m, 2H); Element Analysis,C₂₂H₁₉NO₆.½ H₂O (402): Calculated C, 65.67; H, 4.98; N, 3.48. Found C,66.04; H, 4.87; N, 3.34; IR (KBr): 2923.6, 1738.4, 1627.7, 1511.9,1288.2, 1120.5, 850.5, 713.5 cm⁻¹; EI-MS(m/z): 349(52), 186(100).

INDUSTRIAL APPLICABILITY

The present invention provides benzopyran compounds or salts thereofwhich have the higher insulin-sensitizing activities similar to those ofthiozolidinedione compounds, but the compounds of the present inventiondon't comprise the thiozolidinedione group. Thus, the benzopyrancompounds of the present invention may be developed into the novel drugsfor diabetes without the hepatic toxicity, which are used to control thehigh blood glucose level and inhibit the occurrence of the complicationscaused by the diabetes.

1. A benzopyran compound of formula (I) or its salt:

wherein, the bond between the 3 and 4 position in the formula (I) is asingle bond or a double bond; R₁= a hydrogen atom or a linear orbranched C₁-C₆ alkyl; and R₂= an aromatic heterocyclic group representedby the following formula:


2. A benzopyran compound of formula (I) or its salt of claim 1, whichcompound is selected from the group consisting of: (1)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylicacid methyl ester; (2)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylic acid; (3)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-3,4-dihydro-2-oxo-4H-1-benzopyran-3-carboxylicacid methyl ester; (4)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-2-oxo-2H-1-benzopyran-3-carboxylic acid tert-butyl ester; and (5)7-[2-(5-methyl-2-phenyl-4-oxazole)ethoxyl]-3 ,4-dihydro-2-oxo-4H- 1-benzopyran-3 -carboxylic acid.
 3. A method of treating type II diabetesmellitus comprising administering to a subject an effective amount of acompound of claim 1.